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We used α-Latrotoxin (α-LTx), the main neurotoxic component of the black widow spider venom, which causes degeneration of the neuromuscular junction (NMJ) followed by a rapid and complete regeneration, as a molecular tool to identify by RNA transcriptomics factors contributing to the structural and functional recovery of the NMJ. We found that Urocortin 2 (UCN2), a neuropeptide involved in the stress response, is rapidly expressed at the NMJ after acute damage and that inhibition of CRHR2, the specific receptor of UCN2, delays neuromuscular transmission rescue. Experiments in neuronal cultures show that CRHR2 localises at the axonal tips of growing spinal motor neurons and that its expression inversely correlates with synaptic maturation. Moreover, exogenous UCN2 enhances the growth of axonal sprouts in cultured neurons in a CRHR2-dependent manner, pointing to a role of the UCN2-CRHR2 axis in the regulation of axonal growth and synaptogenesis. Consistently, exogenous administration of UCN2 strongly accelerates the regrowth of motor axon terminals degenerated by α-LTx, thereby contributing to the functional recovery of neuromuscular transmission after damage. Taken together, our results posit a novel role for UCN2 and CRHR2 as a signalling axis involved in NMJ regeneration.

With resurgence of multidrug resistance (MDR) bacteria and no new novel broad-spectrum antibiotic in research pipeline, usage of older generation antibiotics, once discarded due to their toxicity profile are becoming popular again. Often these drugs are the only option left in managing MDR bacteria-related sepsis. Colistin is one of such antibiotic which is often used in recent times after decades of its avoidance due to its diverse toxicity profile. In this case report, we present a rare myasthenic syndrome like neuromuscular complication developed in a patient after receiving colistin for treatment of MDR Klebsiella-related urosepsis., Competing Interests: None declared

Background: Pipecuronium is a steroidal neuromuscular blocking agent. Sugammadex, a relaxant binding γ-cyclodextrin derivative, reverses the effect of rocuronium, vecuronium, and pancuronium. We investigated whether sugammadex reverses moderate pipecuronium-induced neuromuscular blockade (NMB) and the doses required to achieve reversal., Methods: This single-center, randomized, double-blind, 5-group parallel-arm study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX) according to international standards. When the NMB recovered spontaneously to train-of-four count 2, patients randomly received 1.0, 2.0, 3.0, or 4.0 mg/kg of sugammadex or placebo. Recovery time from sugammadex injection to normalized train-of-four (TOF) ratio 0.9 was the primary outcome variable. The recovery time from the sugammadex injection to final T1 was the secondary end point. Postoperative neuromuscular functions were also assessed., Results: Each patient who received sugammadex recovered to a normalized TOF ratio of 0.9 within 5.0 minutes (95% lower confidence interval for the lowest dose 70.1%; for all doses 90.8%) and 79% of these patients reached a normalized TOF ratio 0.9 within 2.0 minutes (95% lower confidence interval for the lowest dose 26.7%; for all doses 63.7%). T1 recovered several minutes after the TOF ratio. No residual postoperative NMB was observed., Conclusions: Sugammadex adequately and rapidly reverses pipecuronium-induced moderate NMB during sevoflurane anesthesia. Once the train-of-four count has spontaneously returned to 2 responses following pipecuronium administration, a dose of 2.0 mg/kg of sugammadex is sufficient to reverse the NMB.

Background: Postoperative residual neuromuscular blockade (NMB), defined as a train-of-four (TOF) ratio of <0.9, is an established risk factor for critical postoperative respiratory events and increased morbidity. At present, little is known about the occurrence of residual NMB in Canada. The RECITE (Residual Curarization and its Incidence at Tracheal Extubation) study was a prospective observational study at 8 hospitals in Canada investigating the incidence and severity of residual NMB., Methods: Adult patients undergoing open or laparoscopic abdominal surgery expected to last <4 hours, ASA physical status I-III, and scheduled for general anesthesia with at least 1 dose of a nondepolarizing neuromuscular blocking agent for endotracheal intubation or maintenance of neuromuscular relaxation were enrolled in the study. Neuromuscular function was assessed using acceleromyography with the TOF-Watch SX. All reported TOF ratios were normalized to the baseline values. The attending anesthesiologist and all other observers were blinded to the TOF ratio (T4/T1) results. The primary and secondary objectives were to determine the incidence and severity of residual NMB (TOF ratio <0.9) just before tracheal extubation and at arrival at the postanesthesia care unit (PACU)., Results: Three hundred and two participants were enrolled. Data were available for 241 patients at tracheal extubation and for 207 patients at PACU arrival. Rocuronium was the NMB agent used in 99% of cases. Neostigmine was used for reversal of NMB in 73.9% and 72.0% of patients with TE and PACU data, respectively. The incidence of residual NMB was 63.5% (95% confidence interval, 57.4%-69.6%) at tracheal extubation and 56.5% (95% confidence interval, 49.8%-63.3%) at arrival at the PACU. In an exploratory analysis, no statistically significant differences were observed in the incidence of residual NMB according to gender, age, body mass index, ASA physical status, type of surgery, or comorbidities (all P > 0.13)., Conclusions: Residual paralysis is common at tracheal extubation and PACU arrival, despite qualitative neuromuscular monitoring and the use of neostigmine. More effective detection and management of NMB is needed to reduce the risks associated with residual NMB.

Background: Intermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulation (RNS) predictors of IMS that would assist in patient management and clinical research., Methods and Findings: Seventy-eight consenting symptomatic patients with organophosphate poisoning were assessed prospectively with daily physical examination and RNS. RNS was done on the right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. The study was conducted as a prospective observational cohort study in the Central Province, Sri Lanka. IMS was diagnosed in ten out of 78 patients using a priori clinical diagnostic criteria, and five of them developed respiratory failure. All ten patients showed progressive RNS changes correlating with the severity of IMS. A decrement-increment was observed at intermediate and high frequencies preceding the onset of clinical signs of IMS. As the patient developed clinical signs of IMS, decrement-increment was progressively noted at low and intermediate frequencies and a combination of decrement-increment and repetitive fade or severe decrement was noted at high frequencies. Severe decrement preceded respiratory failure in four patients. Thirty patients developed forme fruste IMS with less severe weakness not progressing to respiratory failure whose RNS was characterized by decrement-increment or a combination of decrement-increment and repetitive fade but never severe decrements., Conclusions: Characteristic changes in RNS, preceding the development of IMS, help to identify a subgroup of patients at high risk of developing respiratory failure. The forme fruste IMS with the characteristic early changes on RNS indicates that IMS is a spectrum disorder. RNS changes are objective and precede the diagnosis and complications of IMS. Thus they may be useful in clinical management and research.

Acute organophosphate insecticide poisoning can manifest 3 different phases of toxic effects, namely, acute cholinergic crisis, intermediate syndrome (IMS), and delayed neuropathy. Among them, IMS has been considered as a major contributing factor of organophosphate-related morbidity and mortality because of its frequent occurrence and probable consequence of respiratory failure. Despite a high incidence, the pathophysiology that underlies IMS remains unclear. Previously proposed mechanisms of IMS include different susceptibility of various cholinergic receptors, muscle necrosis, prolonged acetylcholinesterase inhibition, inadequate oxime therapy, downregulation or desensitization of postsynaptic acetylcholine receptors, failure of postsynaptic acetylcholine release, and oxidative stress-related myopathy. The clinical manifestations of IMS typically occur within 24 to 96 hours, affecting conscious patients without cholinergic signs, and involve the muscles of respiration, proximal limb muscles, neck flexors, and muscles innervated by motor cranial nerves. With appropriate therapy that commonly includes artificial respiration, complete recovery develops 5-18 days later. Patients with atypical manifestations of IMS, especially a relapse or a continuum of acute cholinergic crisis, however, were frequently reported in clinical studies of IMS. The treatment of IMS is mainly supportive. Nevertheless, because IMS generally concurs with severe organophosphate toxicity and persistent inhibition of acetylcholinesterase, early aggressive decontamination, appropriate antidotal therapy, and prompt institution of ventilatory support should be helpful in ameliorating the magnitude and/or the incidence of IMS. Although IMS is well recognized as a disorder of neuromuscular junctions, its exact etiology, incidence, and risk factors are not clearly defined because existing studies are largely small-scale case series and do not employ a consistent and rigorous definition of IMS. Without a clear understanding of the pathophysiology of IMS, specific therapy is not available. The prognosis of IMS, however, is likely to be favorable if respiratory failure can be promptly recognized and treated accordingly.

Background: Postoperative residual curarization (PORC) after surgery is common and its detection has a high error rate. Artificial neural networks are being used increasingly to examine complex data. We hypothesized that a neural network would enhance prediction of PORC., Methods: In 40 previously reported patients, neuromuscular function, neuromuscular block/antagonist usage and time intervals were recorded throughout anaesthesia until tracheal extubation by an observer uninvolved in patient care. PORC was defined as significant 'fade' (train of four <0.7) at extubation. Neuromuscular function was classified as PORC (value=1) or no PORC (value=0). A back-propagation neural network was trained to assign similar values (0, 1) for prediction of PORC, by examining the impact of (i) the degree of spontaneous recovery at reversal, and (ii) the time since pharmacological reversal, using the jackknife method. Successful prediction was defined as attainment of a predicted value within 0.2 of the target value., Results: Twenty-six patients (65%) had PORC at tracheal extubation. Clinical detection of PORC had a sensitivity of 0 and specificity of 1, with an indeterminate positive predictive value and a negative predictive value of 0.35. Using the artificial neural network, one patient with residual block and one with adequate neuromuscular function were incorrectly classified during the test phase, with no indeterminate predictions, giving an artificial neural network sensitivity of 0.96 (chi(2)=44, P<0.001) and specificity of 0.92 (P=1), with a positive predictive value of 0.96 and a negative predictive value of 0.93 (chi(2)=12, P<0.001)., Conclusions: Neural network-based prediction, using readily available clinical measurements, is significantly better than human judgement in predicting recovery of neuromuscular function.